We are studying the secretin-VIP family of G-protein coupled receptors. This recently identified group of receptors has virtually no amino acid sequence conservation with the remaining majority of G-protein coupled receptors (the rhodopsin family). Much less is known about structure-function relationships and effector system coupling of the secretin-VIP family receptors. Their cloning has also raised new questions about their physiological roles and created tools for study of their distribution, regulation and pharmacology. We are currently pursuing the physiological role of the PTH2 receptor which we discovered 3 years ago. The receptor is most abundant in the brain but we detect no PTH, its only known ligand, in the CNS. We have demonstrated the existence of a new neuropeptide, selective for the PTH2 receptor in hypothalamic extracts. We are working on its purification. We have performed a large scale hypothalamic extraction and have purified an active peptide to apparent homogeneity, based on its absorption profile during chromatography and analysis using mass spectroscopy. We are currently attempting to define its amino acid sequence so that the peptide can be synthesized for functional studies and to facilitate cloning of its gene. We have developed an antibody which selectively recognizes the PTH2 receptor and are using it to study the distribution and regulation of PTH2 receptor protein. The peripheral distribution suggests that it may have a number of endocrine functions. In the brain the receptor is present in areas involved in adaptive functions, including parts of the limbic system, areas projecting to and receiving connections from the hippocampus and several parts of the medial hypothalamus. The hypothalamic distribution suggests that it may be involved in the regulation of pituitary hormones, and we have initiated experiments to test this hypothesis.